A fraction of patients referred for tumor-only complex molecular profiling may harbor germline variants in genes associated with the development of hereditary cancer syndromes (HCS). Bioinformatic management and reporting of such incidental germline findings are not standardized.
Data from NGS sequencing of tumor-only samples from patients referred for complex molecular profiling were analyzed in order to identify germline variants in HCS-associated genes. Analysis of variant origin was performed employing bioinformatic algorithms followed by manual curation. If possible, variant origin was validated by Sanger sequencing using patients’ normal tissue. Variants’ pathogenicity was assessed according to ACMG/AMP.
NGS data from 183 patients (75 men [41.0%]; mean [SD] age, 57.7 [13.3] years) were obtained. The most common tumor types were colorectal (19%), pancreatic (13%), and lung cancer (10%). We detected 56 sequencing variants (40 patients) in genes associated with HCS. Of them, 17 (14 patients) were predicted to be of germline origin with 6 variants interpreted as pathogenic (PV) or likely pathogenic (LPV) and 9 as variants of uncertain significance (VUS). Bioinformatics prediction of variant origin was concordant with manual curation for the 41 (97%) missense variants in HCS associated genes. Based on the results of our study we estimate that Sanger sequencing using a patient's normal tissue would be required in ∼1-7% of cases (PV or LPV found in HCS genes) while referring for genetic counseling in ∼2-15% of cases (PV, LPV or VUS found in HCS genes).
Incidental findings of pathogenic germline variants are common in data from cancer patients referred for complex molecular profiling. We propose an algorithm for the management of variants in genes associated with HCS.
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E. Rozhavskaya, M. Sharova, J. Shaykhutdinova, V. Mileyko: Financial Interests, Personal, Affiliate: Atlas Oncology Diagnostics. A. Baranova: Financial Interests, Institutional, Advisory Board: Atlas Oncology Diagnostics. All other authors have declared no conflicts of interest.